TY - JOUR
T1 - Clinical and neurophysiological characteristics of heterozygous NPC1 carriers
AU - Benussi, Alberto
AU - Cotelli, Maria S.
AU - Cantoni, Valentina
AU - Bertasi, Valeria
AU - Turla, Marinella
AU - Dardis, Andrea
AU - Biasizzo, Jessica
AU - Manenti, Rosa
AU - Cotelli, Maria
AU - Padovani, Alessandro
AU - Borroni, Barbara
PY - 2019
Y1 - 2019
N2 - Niemann-Pick disease type C (NPC) is an uncommon lysosomal storage disorder, which is characterized neuropathologically by cholinergic dysfunction and presents clinically with a broad series of neurological signs and symptoms. NPC is inherited as an autosomal recessive trait, caused by mutations in the NPC1 or NPC2 genes. However, recent reports have raised concerns on heterozygous NPC1 gene mutation carriers, which historically have been considered as clinically unaffected, occasionally presenting with clinical parkinsonian syndromes or dementia. In the present study, we aimed at comprehensively assessing clinical, biochemical, and neurophysiological features in heterozygous NPC1 gene mutation carriers. We assessed cholinergic intracortical circuits with transcranial magnetic stimulation, executive functions and plasma oxysterol levels in two families comprising two monozygotic twins with a homozygous NPC1 p.P888S mutation, four patients with a compound heterozygous p.E451K and p.G992W mutation, 10 heterozygous NPC1 p.P888S carriers, 1 heterozygous NPC1 p.E451K carrier, and 11 noncarrier family members. We observed a significant impairment in cholinergic circuits, evaluated with short-latency afferent inhibition (SAI), and executive abilities in homozygous/compound heterozygous patients and heterozygous asymptomatic NPC1 carriers, compared to noncarriers. Moreover, we reported a significant correlation between executive functions performances and both plasma oxysterol levels and neurophysiological parameters. These data suggest that heterozygous NPC1 carriers show subclinical deficits in cognition, possibly mediated by an impairment of cholinergic circuits, which in turn may mediate the onset of neurological disorders in a subset of patients.
AB - Niemann-Pick disease type C (NPC) is an uncommon lysosomal storage disorder, which is characterized neuropathologically by cholinergic dysfunction and presents clinically with a broad series of neurological signs and symptoms. NPC is inherited as an autosomal recessive trait, caused by mutations in the NPC1 or NPC2 genes. However, recent reports have raised concerns on heterozygous NPC1 gene mutation carriers, which historically have been considered as clinically unaffected, occasionally presenting with clinical parkinsonian syndromes or dementia. In the present study, we aimed at comprehensively assessing clinical, biochemical, and neurophysiological features in heterozygous NPC1 gene mutation carriers. We assessed cholinergic intracortical circuits with transcranial magnetic stimulation, executive functions and plasma oxysterol levels in two families comprising two monozygotic twins with a homozygous NPC1 p.P888S mutation, four patients with a compound heterozygous p.E451K and p.G992W mutation, 10 heterozygous NPC1 p.P888S carriers, 1 heterozygous NPC1 p.E451K carrier, and 11 noncarrier family members. We observed a significant impairment in cholinergic circuits, evaluated with short-latency afferent inhibition (SAI), and executive abilities in homozygous/compound heterozygous patients and heterozygous asymptomatic NPC1 carriers, compared to noncarriers. Moreover, we reported a significant correlation between executive functions performances and both plasma oxysterol levels and neurophysiological parameters. These data suggest that heterozygous NPC1 carriers show subclinical deficits in cognition, possibly mediated by an impairment of cholinergic circuits, which in turn may mediate the onset of neurological disorders in a subset of patients.
KW - Acetylcholine
KW - Cognition
KW - Executive functions
KW - Heterozygous
KW - Niemann-Pick disease type C
KW - Short latency afferent inhibition
KW - Transcranial magnetic stimulation
KW - Acetylcholine
KW - Cognition
KW - Executive functions
KW - Heterozygous
KW - Niemann-Pick disease type C
KW - Short latency afferent inhibition
KW - Transcranial magnetic stimulation
UR - http://hdl.handle.net/10807/151611
U2 - 10.1002/jmd2.12059
DO - 10.1002/jmd2.12059
M3 - Article
SN - 2192-8304
VL - 49
SP - 80
EP - 88
JO - JIMD Reports
JF - JIMD Reports
ER -